Chemokines constitute a family of small pro-inflammatory cytokines with leukocyte chemotactic and activating properties. Depending on the position of the first cysteines, the chemokine family can be divided in C—C, C—X—C and C—X3—C chemokines (Baggiolini M. et al., 1994; Baggiolini M. et al., 1997 and Taub D. et al., 1996).
Many C—X—C chemokines such as interleukin-8 (IL-8) are chemotactic for neutrophils, while C—C chemokines, such as monocyte chemotactic protein-3 (MCP-3), are active on a variety of leukocytes including monocytes, lymphocytes, eosinophils, basophils, NK cells and dendritic cells.
The NH2-terminal domain of chemokines is involved in receptor-binding and NH2-terminal processing can either activate chemokines or render chemokines completely inactive.
The C—X—C chemokine platelet basic protein becomes a neutrophil chemotactic peptide (NAP-2) only after removal of the 24 NH2-terminal residues (Walz A. et al., 1989 and Van Damme J. et al., 1990).
Deletion of up to 8 NH2-terminal residues from IL-8 results in an enhanced chemotactic activity, but further cleavage of the Glu-Leu-Arg motif, which is located in front of the first Cys in all neutrophil chemotactic C—X—C chemokines, causes complete inactivation (Clark-Lewis I. et al., 1991).
Similar NH2-terminal proteolysis (up to 8 amino acids) of another C—X—C chemokine, granulocyte chemotactic protein-2 (GCP-2), has no effect on the neutrophil chemotactic activity (Proost P. et al, 1993a).
The synthetical C—C chemokines MCP-1, MCP-3 and RANTES missing the 8 to 9 NH2-terminal amino acids are inactive on monocytes and are useful as receptor antagonists (Gong J. et al., 1996; and Gong J. et al., 1995).
Extension of RANTES with one methionine results in complete inactivation of the molecule and Met-RANTES behaves as an antagonist for the authentic RANTES (Proudfoot A. E. et al., 1996).
The clone of human MCP-2 (Monocyte Chemoattractant Protein-2) has been isolated by differential library screening with cDNA probes derived from stimulated versus resting peripheral blood lymphocytes (PBL) (it was initially called “HC14”, Chang H. C. et al., 1989). The cDNA-derived protein sequence was identical to that of purified natural MCP-2; however, a putative allelic variant has also been isolated, in which Gln 46 replaces Lys 46 (Van Coillie et al., 1997).
MCP-2 has also been synthesized by solid-phase chemistry (Proost P. et al., 1995).